What medications are most likely to cause Acute Kidney Injury (AKI) and where on the nephron do they typically cause injury?

Common Medications Causing Acute Kidney Injury and Their Mechanisms

The most common medications causing AKI are NSAIDs, ACE inhibitors/ARBs, diuretics, aminoglycosides, and certain antimicrobials, each affecting specific parts of the nephron through distinct mechanisms of injury. 1, 2

Medication Classes and Their Mechanisms of Nephrotoxicity

1. Hemodynamically-Mediated AKI (Functional/Pre-renal)

• NSAIDs

  • Mechanism: Inhibit prostaglandin synthesis → afferent arteriole vasoconstriction → decreased renal perfusion
  • Site of injury: Glomerular hemodynamics
  • Risk factors: Volume depletion, elderly, pre-existing kidney disease 1, 2

• ACE Inhibitors/ARBs

  • Mechanism: Block efferent arteriole vasoconstriction → decreased glomerular filtration pressure
  • Site of injury: Glomerular hemodynamics
  • High risk: Bilateral renal artery stenosis, volume depletion 1

• Diuretics

  • Mechanism: Volume depletion → decreased renal perfusion
  • Site of injury: Pre-renal
  • Risk factors: Elderly, heart failure 1, 3

• "Triple Whammy" Combination

  • Concurrent use of NSAIDs + ACE inhibitors/ARBs + diuretics
  • Dramatically increases AKI risk through combined hemodynamic effects 1

2. Direct Tubular Toxicity

• Aminoglycosides (gentamicin, tobramycin, amikacin)

  • Mechanism: Cellular uptake via endocytosis → lysosomal damage → tubular cell death
  • Site of injury: Proximal tubule
  • Warning: FDA black box warning for nephrotoxicity 4, 5

• Amphotericin B

  • Mechanism: Disrupts cell membrane integrity → tubular damage
  • Site of injury: Distal tubule
  • Risk factors: Cumulative dose, dehydration 6, 5

• Vancomycin

  • Mechanism: Direct tubular toxicity and cast formation
  • Site of injury: Proximal tubule
  • Risk factors: High trough levels, prolonged therapy 6, 5

• Cisplatin and other chemotherapeutics

  • Mechanism: Direct cellular toxicity, mitochondrial damage
  • Site of injury: Proximal tubule
  • Risk factors: High doses, prior kidney disease 2, 6

3. Acute Interstitial Nephritis (AIN)

• Antibiotics (beta-lactams, sulfonamides, fluoroquinolones)

  • Mechanism: Hypersensitivity reaction → interstitial inflammation
  • Site of injury: Tubulointerstitium
  • Clinical features: Fever, rash, eosinophilia (classic triad) 7, 6

• Proton Pump Inhibitors

  • Mechanism: Delayed hypersensitivity reaction
  • Site of injury: Tubulointerstitium
  • Timing: Can occur months after starting therapy 2, 7

• Immune Checkpoint Inhibitors

  • Mechanism: Immune-mediated inflammation
  • Site of injury: Tubulointerstitium
  • Management: Often requires steroid therapy 2, 6

4. Intratubular Obstruction/Crystal Nephropathy

• Acyclovir

  • Mechanism: Crystal precipitation in tubules → obstruction
  • Site of injury: Distal tubule
  • Prevention: Adequate hydration, slower infusion 6, 8

• Methotrexate

  • Mechanism: Crystal formation in acidic urine
  • Site of injury: Distal tubule
  • Prevention: Alkalinization of urine, hydration 2, 6

• Indinavir, Sulfadiazine

  • Mechanism: Intratubular crystal formation
  • Site of injury: Collecting ducts
  • Risk factors: High doses, dehydration 6, 8

Risk Factors for Drug-Induced AKI

• Pre-existing kidney disease (GFR <60 ml/min/1.73 m²)
• Advanced age
• Volume depletion/dehydration
• Diabetes mellitus
• Heart failure
• Multiple nephrotoxic medications (each additional nephrotoxin increases AKI risk by 53%)
• High drug doses or prolonged therapy 1, 2

Prevention Strategies

• Avoid concurrent use of multiple nephrotoxic agents
• Ensure adequate hydration
• Use lowest effective dose for shortest duration
• Temporary discontinuation during acute illness with volume depletion
• Regular monitoring of renal function
• Dose adjustment based on kidney function 1, 2

Clinical Pearls

• Drug-induced AKI accounts for approximately 20-25% of all AKI cases in hospitalized patients 1, 3
• Aminoglycosides, amphotericin B, and vancomycin are among the most nephrotoxic antimicrobials 4, 5
• Recovery from drug-induced AKI typically occurs after discontinuation of the offending agent, but may take weeks to months
• Some medications (e.g., NSAIDs) can cause functional changes without structural damage, while others cause direct tubular injury 1, 7
• Contrast media can cause AKI through vasoconstriction and direct tubular toxicity, particularly in high-risk patients 1

Understanding the mechanisms and sites of injury for different nephrotoxic medications helps guide prevention strategies and management decisions when AKI occurs.